Compounds useful as antimicrobial agents

ABSTRACT

There are described new 2-cyclohexan-1-yl-amine derivatives of formula (I) ##STR1## in which A, R 1 , R 2 , R 3  and R 4  have the meaning given in the description, and processes for their preparation. 
     The compounds of the formula (I) are used as antimicrobial agents.

The present invention relates to the use of substituted2-cyclohexan-1-yl-amine derivatives, some of which are known, asantimicrobial agents in plant protection, mainly as fungicides and asantimycotics, as well as new substituted 2-cyclohexan-1-yl-aminederivatives, and a plurality of processes for their preparation.

It is already known that certain tetrahydrophthalimides such as, forexample, cis-N-[(trichloromethyl)thio]-4-cyclohexene-1,2-dicarboimide,have fungicidal properties (cf. for example, Science, (Washington) 115.84 (1952); U.S. Pat. No. 2,553,770).

However, the action of these compounds is not always entirelysatisfactory in all fields of application, in particular when smallamounts and low concentrations are applied.

Furthermore, it is also already known that 2-cycloalkenylaminederivatives and their salts, such as, for exampleN-2-cyclohexen-1-yl-2,2-dimethyl-propionamide, have fungicidalproperties (cf. EP-OS (European Published Specification) 0,128,006).

It has now been found that the substituted 2-cyclohexan1-yl-aminederivatives, some of which are known, of the formula (I) ##STR2## inwhich

R¹ represents hydrogen, halogen or alkyl,

R² represents formyl, hydroxyalkyl, or one of the radicals ##STR3##

R³ and R⁴ are identical or different and in each case representhydrogen, alkyl, alkoxy, or represent unsubstituted or substituted aryl,or represent unsubstituted or substituted aralkyl, or representunsubstituted or substituted heteroaryl or alkoxyalkyloxy,

R⁵ represents alkyl or alkoxy,

R⁶ represents hydroxyl, hydroxyalkyloxy, halogenoalkyloxy, alkoxy,alkoxyalkyloxy, in each case unsubstituted or substitutedalkenylalkyloxy, alkinylalkyloxy and cycloalkyloxy, unsubstituted orsubstituted aralkyloxy, unsubstituted or substituted aryloxy,unsubstituted or substituted aralkyl, alkylthio, unsubstituted orsubstituted arylthio, or represents a group --OM, --NR⁸ R⁹ or--O--Z--NR⁸ R⁹,

R⁷ represents hydrogen or alkyl,

R⁸ represents hydrogen, alkyl or unsubstituted or substituted aryl,

R⁹ represents hydrogen, alkyl or unsubstituted or substituted aryl,

M represents hydrogen, or represents an equivalent of a correspondingalkali metal cation, alkaline earth metal cation or ammonium cation,

X and X¹ are identical or different and represent oxygen or sulphur,

A represents hydrogen or an amino protective group, and

Z represents a straight-chain or branched alkyl chain,

and their acid addition salts and metal salt complexes have powerfulbiological properties.

The compounds of the formula (I) contain 1 to 4 centres of chirality andcan therefore exist in various mixtures of enantiomers and diastereomerswhich, if desired, can be separated in the customary fashion. Theinvention also claims the use of the pure enantiomers and diastereomersas well as the use of the mixtures.

For simplicity's sake, the following text will always mention the use ofcompounds of the formula (I), even though this is understood as meaningthe pure compounds as well as the mixtures with various proportions ofisomeric, enantiomeric and diastereomeric compounds.

Surprisingly, the substituted 2-cyclohexan-1-yl-amine derivatives of theformula (I), some of which are known, and their acid addition salts andmetal salt complexes have outstanding fungicidal properties when appliedin appropriate concentrations. In addition, the substituted2-cyclohexan-1-yl-amine derivatives of the formula (I), some of whichare known, also have very good antimicrobial properties when applied inappropriate concentrations.

Formula (I) provides a general definition of the substituted2-cyclohexan-1-yl-amine derivatives to be used according to theinvention.

Unless defined otherwise, the meanings in the general formulae in thefollowing text are:

Alkyl - straight-chain or branched alkyl having 1 to 8, preferably 1 to6, in particular 1 to 4, carbon atoms. The following may be mentioned byway of example and as preferred: optionally substituted methyl, ethyl,n.- and i.-propyl and n-, i-, s- and t-butyl.

Alkoxy - unsubstituted or substituted, straight-chain or branched alkoxyhaving 1 to 8, preferably 1 to 6, in particular 1 to 4, carbon atoms.The following may be mentioned by way of example and as preferred:optionally substituted methoxy, ethoxy, n.- and i.-propoxy and n-, i-,s- and t-butoxy.

Aryl - preferably unsubstituted or substituted phenyl or naphthyl, inparticular phenyl.

Aralkyl and aralkoxy - aralkyl or aralkoxy, each of which has preferably6 or 10, in particular 6, carbon atoms in the aryl moiety (preferablyphenyl or naphthyl, in particular phenyl) and preferably 1 to 8, inparticular 1 to 6, carbon atoms in the alkyl moiety, it being possiblefor the alkyl moiety to be straight-chain or branched, and each of whichis unsubstituted or substituted in the aryl moiety and/or alkyl moiety.The following may be mentioned by way of example and as preferred:optionally substituted benzyl and phenylethyl, or benzyloxy andphenylethyloxy, respectively.

Unsubstituted or substituted heterocyclic radicals in the generalformulae denote heteroaromatic 5-6-membered rings having preferably 1 to3, in particularly 1 or 2, identical or different hetero atoms. Heteroatoms are oxygen, sulphur or nitrogen. The following may be mentioned byway of example and as preferred: pyrrolidinyl, piperidinyl, furyl,thienyl, pyrazolyl, imidazolyl, 1,2,3- and 1,2,4-triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, 1,3,4- and 1,2,4-oxadiazolyl,azepinyl, pyrrolyl, isopyrrolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl and 1,2,3-, 1,2,4-, 1,2,5- and 1,3,4-thiadiazolyl.

Halogen in the general formulae preferably denotes fluorine, chlorine,bromine and iodine, in particular fluorine, chlorine and bromine, andparticularly preferably fluorine and chlorine.

The optionally substituted radicals of the general formulae can carryone or more, preferably 1 to 3, in particular 1 or 2, identical ordifferent substituents. Examples of preferred substituents which may bementioned are:

Alkyl having preferably 1 to 4, in particular 1 or 2, carbon atoms, suchas methyl, ethyl, n.- and i.-propyl and n.-, i.- and t.-butyl; alkoxyhaving preferably 1 to 4, in particular 1 or 2, carbon atoms, such asmethoxy, ethoxy, n.- and i.-propyloxy and n.-, i.-, sec.- andt.-butyloxy; alkylthio having preferably 1 to 4, in particular 1 or 2,carbon atoms, such as methylthio, ethylthio, n.- and i.-propylthio andn.-, i.-, sec.- and t.-butylthio; halogenoalkyl, halogenoalkoxy andhalogenoalkylthio, each of which has preferably 1 to 4, in particular 1or 2, carbon atoms and preferably 1 to 9, in particular 1 to 5. halogenatoms, the halogen atoms being identical or different and preferablybeing fluorine, chlorine or bromine, in particular fluorine, such astrifluoromethyl, trifluoromethoxy and trifluoromethylthio; hydroxyl;halogen, preferably fluorine, chlorine, bromine and iodine, inparticular fluorine, chlorine and bromine; cyano; nitro; amino;dialkylamino having preferably 1 to 4, in particular 1 or 2, carbonatoms per alkyl group, such as methyl-ethyl-amino, andmethyl-n.-butylamino; carboxyl.

Preferred compounds of the formula (I) which are used are those in which

R¹ represents hydrogen, halogen and straight-chain or branched alkylhaving 1 to 6 carbon atoms,

R² represents formyl, straight-chain or branched hydroxyalkyl having 1to 8 carbon atoms in the alkyl moiety, or represents one of the radicals##STR4##

R³ and R⁴ are identical or different and in each case representhydrogen, in each case straight-chain or branched alkyl or alkoxy having1 to 8 carbon atoms, alkoxyalkyloxy having 1 to 8 carbon atoms in eachof the individual alkyl moieties, or represent aryl or aralkyl, each ofwhich has 6 to 10 carbon atoms in the aryl moiety and if appropriate 1to 4 carbon atoms in the alkyl moiety, and each of which isunsubstituted or monosubstituted to pentasubstituted in the aryl moietyby identical or different substituents, suitable aryl substituentsbeing: halogen, nitro, cyano, amino, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy or C₁-C₄ -alkylthio, halogeno-(C₁ -C₄)-alkyl, halogeno-(C₁ -C₄)-alkoxy,halogeno-(C₁ -C₄)-alkylthio, each of which has 1 to 9 identical ordifferent halogen atoms, and di-(C₁ -C₄)-alkylamino; furthermorerepresents a heteroarylic 5- or 6-membered ring which is unsubstitutedor monosubstituted to pentasubstituted by identical or differentsubstituents and which can contain 1 to 3 oxygen, sulphur and/ornitrogen atoms as further hetero atoms, suitable substituents for theheterocycle in each case being: halogen, nitro, cyano, amino, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, halogeno(C₁ -C₄)-alkyl,halogeno-(C₁ -C₄)-alkoxy, halogeno(C₁ -C₄)-alkylthio, each of which has1 to 9 identical or different halogen atoms, and di-(C₁ -C₄)-alkylamino,

R⁵ represents in each case straight-chain or branched alkyl or alkoxyhaving 1 to 6 carbon atoms,

R⁶ represents hydroxyl, straight-chain or branched hydroxyalkyloxy,having 1 to 8 carbon atoms, straight-chain or branched halogenoalkyloxyhaving 1 to 8 carbon atoms and 1 to 17 identical or different halogenatoms, or represents alkenylalkyloxy, alkinylalkyloxy and cycloalkyloxy,each of which has 3 to 6 carbon atoms, and each of which isunsubstituted or monosubstituted to polysubstituted by identical ordifferent halogen substituents, or represents in each casestraight-chain or branched alkoxy or alkylthio having 1 to 6 carbonatoms, straight-chain or branched alkoxyalkyloxy having 1 to 6 carbonatoms in the alkoxy and alkyl moieties, or represents aryloxy, arylthio,aralkyl or aralkyloxy, each of which has 6 to 10 carbon atoms in thearyl moiety and if appropriate 1 to 8 carbon atoms in the alkyl moietyand each of which is unsubstituted or monosubstituted topentasubstituted in the aryl moiety by identical or differentsubstituents, suitable aryl substituents being the aryl substituentsmentioned under R³, or represents a group --OM, --NR⁸ R⁹ or --O--Z--NR⁸R⁹,

R⁷ represents hydrogen or straight-chain or branched alkyl having 1 to 6carbon atoms,

R⁸ and R⁹ are identical or different and represent hydrogen,straight-chain or branched alkyl having 1 to 6 carbon atoms, or arylwhich has 6 to 10 carbon atoms and which is unsubstituted ormonosubstituted to pentasubstituted by identical or differentsubstituents, suitable aryl substituents being the aryl substituentsmentioned under R³,

M represents hydrogen, or represent an equivalent of a correspondingalkali metal cation, alkaline earth metal cation or ammonium cation,

X and X¹ are identical or different and represent oxygen or sulphur,

A represents hydrogen or an amino protective group, and

Z represents a straight-chain or branched alkyl chain having 1 to 8carbon atoms.

Other compounds preferably to be used according to the invention arealso addition products of acids and those substituted2-cyclohexan-1-yl-amine derivatives of the formula (I) in which R¹, R²,R³ and R⁴ have those meanings which have already been mentioned inconnection with the description of the substances to be used accordingto the invention as being preferred for these substituents.

The acids which can be added on preferably include hydrohalic acids suchas, for example, hydrochloric acid and hydrobromic acid, in particularhydrochloric acid, furthermore phosphoric acid, nitric acid, mono- andbifunctional carboxylic acids and hydroxycarboxylic acids such as, forexample, acetic acid, trifluoroacetic acid, maleic acid, succinic acid,fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acidand lactic acid, oleic acid, stearic acid, or benzoic acid which isoptionally monosubstituted to polysubstituted by nitro or halogen, orgluconic acid, ascorbic acid, malic acid, sulphamic acid, sulphonicacids such as, for example, p-toluenesulphonic acid,1,5-naphthalenedisulphonic acid and methanesulphonic acid, and alsoimides such as, for example, phthalimide, saccharin and thiosaccharin.

Other compounds to be preferably used according to the invention arefurthermore addition products of salts of metals of main group I, II andIII and of tin, also furthermore salts of metals of sub-group I, II, VIIand VIII of the Periodic Table of the Elements and those substituted2-cyclohexan-1-yl-amine derivatives of the formula (I) in which R¹, R²,R³ and R⁴ have the meanings which have already been mentioned inconnection with the description of the substances of the formula (I) tobe used according to the invention as being preferred for thesesubstituents.

In this context, salts of copper, zinc, manganese, magnesium, calcium,tin, iron, cobalt and of nickel are particularly preferred. Suitableanions of these salts are those which are derived from those acids whichlead to physiologically acceptable addition products. Acids of this typewhich are particularly preferred in this connection are the hydrohalicacids such as, for example, hydrochloric acid and hydrobromic acid,further phosphoric acid, nitric acid and sulphuric acid.

Compounds of the formula (I) which are particularly preferably used arethose in which

R¹ represents hydrogen, fluorine, chlorine, bromine or straight-chain orbranched alkyl having 1 to 4 carbon atoms,

R² represents formyl, straight-chain or branched hydroxyalkyl having 1to 4 carbon atoms in the alkyl moiety, or represents one of the radicals##STR5##

R³ and R⁴ are identical or different and in each case representhydrogen, in each case straight-chain or branched alkyl or alkoxy having1 to 6 carbon atoms, alkoxyalkyloxy having 1 to 6 carbon atoms in eachof the individual alkyl moieties, or represent phenyl or phenylalkyl,having, where appropriate, 1 or 2 carbon atoms in the alkyl moiety, eachof which is unsubstituted or monosubstituted to pentasubstituted in thephenyl moiety by identical or different substituents, suitable phenylsubstituents being: fluorine, chlorine, bromine, nitro, cyano, amino, C₁-C₂ -alkyl, C₁ C₃ -alkoxy or C₁ -C₂ -alkylthio, halogeno(C₁ -C₂)-alkyl,halogeno-(C₁ -C₂)-alkoxy and halogeno(C₁ -C₂)-alkylthio, each of whichhas 1 to 5 identical or different fluorine and/or chlorine atoms,furthermore represent a heterocyclic five- or six-membered group fromthe series comprising furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3- or 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,4- or1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl,each of which is, if appropriate, bonded via a methylene group and eachof which is unsubstituted or monosubstituted to trisubstituted byidentical or different substituents, suitable substituents for theheterocycle in each case being: fluorine, chlorine, bromine, nitro,cyano, amino, C₁ -C₂ -alkyl, C₁ -C₂ -alkoxy or C₁ -C₂ -alkylthio,halogeno-(C₁ -C₂)-alkyl, halogeno-(C₁ -C₂)-alkoxy, halogeno-(C₁-C₂)-alkylthio each of which has 1 to 5 identical or different fluorineand/or chlorine atoms, and di-(C₁ -C₂)-alkylamino,

R⁵ represents in each case straight-chain or branched alkyl or alkoxyhaving 1 to 4 carbon atoms,

R⁶ represents hydroxyl, straight-chain or branched hydroxylalkyloxyhaving 1 to 6 carbon atoms, straight-chain or branched halogenoalkyloxyhaving 1 to 6 carbon atoms and 1 to 13 identical or different halogenatoms, or represents alkenylalkyloxy, alkinylalkyloxy and cycloalkyloxy,having 3 to 6 carbon atoms and each of which is unsubstituted ormonosubstituted to trisubstituted by identical or different substituentsfrom the series comprising fluorine, chlorine and bromine, or representsin each case straight-chain or branched alkoxy or alkylthio having 1 to4 carbon atoms, or straight-chain or branched alkoxyalkyloxy having 1 to4 carbon atoms in each of the alkoxy or alkyl moieties, or representsphenyloxy, phenylthio, phenylalkyl or phenylalkyloxy, having, whereappropriate, 1 to 6 carbon atoms in the alkyl moiety, each of which isunsubstituted or monosubstituted to pentasubstituted in the phenylmoiety by identical or different substituents, suitable phenylsubstituents being the phenyl substituents mentioned under R³, orrepresents a group --OM, --NR⁸ R⁹ or --O--Z--NR⁸ R⁹,

R⁷ represents hydrogen or straight-chain or branched alkyl having 1 to 4carbon atoms,

R⁸ and R⁹ are identical or different and represent hydrogen,straight-chain or branched alkyl having 1 to 4 carbon atoms, or phenylwhich is unsubstituted or monosubstituted to pentasubstituted byidentical or different substituents, suitable phenyl substituents beingthe phenyl substituents mentioned under R³,

M represents hydrogen, or represents an equivalent of a correspondingsodium cation, potassium cation or ammonium cation,

X and X¹ are identical or different and represent oxygen or sulphur,

A represents hydrogen or an amino protective group and

Z represents a straight-chain or branched alkyl chain having 1 to 6carbon atoms.

The term "amino protective group" is generally known and relates togroups which are suitable for protecting (blocking) an amino group fromchemical reactions, but which are readily detachable after the desiredreaction has been carried out at different sites of the molecule.Typical representatives of such groups are, in particular, unsubstitutedor substituted acyl groups, aryl groups, for example DNP(2,4-dinitrophenyl), aralkoxymethyl groups, for example BOM(N-(benzyloxy)methyl) or aralkyl groups (for example benzyl,4-nitrobenzyl or triphenylmethyl). Since the amino protective groups areremoved after the desired reaction (or reaction sequence), their natureand size is usually not crucial; however, those having 1 - 20, inparticular 1 - 8, carbon atoms are preferred. The term "acyl group" inconnection with the present invention must be seen in the broadestsense. It embraces acyl groups which are derived from aliphatic,araliphatic, aromatic or heterocyclic carboxylic acids or sulphonicacids, and, in particular alkoxycarbonyl, aryloxycarbonyl, and mainlyaralkoxycarbonyl groups. Examples of acyl groups of this type arealkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such asphenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such asPOA (phenoxyacetyl); alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC(tert.-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such asCBZ ("carbobenzoxy") and 4-methoxybenzyloxycarbonyl. Preferred aminoprotective groups are benzyl, acetyl, methoxycarbonyl, allyloxycarbonyl,trichloroethyloxycarbonyl, (±)-menthyloxycarbonyl, tert-butoxycarbonyland benzyloxycarbonyl.

Another subject of the application are new substituted2-cyclohexan-1-yl-amine derivatives of the formula (Ia) ##STR6## inwhich

R^(1') represents hydrogen, halogen or alkyl,

R^(2') represents formyl, hydroxyalkyl, or represents one of theradicals ##STR7##

R^(3'), R^(4'), R^(5') and R^(6') are identical or different and in eachcase represent hydrogen, alkyl or alkoxy, or represent unsubstituted orsubstituted aryl, or represent unsubstituted or substituted aralkyl, orrepresent unsubstituted or substituted heteroaryl or alkoxyalkyloxy,

where at least two of the radicals R^(3'), R^(4'), R^(5') or R^(6')represent hydrogen,

R^(7') represents alkyl or alkoxy

R^(8') represents hydroxyl, hydroxyalkyloxy, halogenoalkyloxy, alkoxy,alkoxyalkyloxy, in each case unsubstituted or substitutedalkenylalkyloxy, alkinylalkyloxy and cycloalkyloxy, unsubstituted orsubstituted aralkyloxy, unsubstituted or substituted aryloxy,unsubstituted or substituted aralkyl, alkylthio, unsubstituted orsubstituted arylthio, or represents a group --O--Z--NR^(10') R^(11'),--NR^(10') R^(11') or --OM,

R^(9') represents hydrogen or alkyl

R^(10') and R^(11') are identical or different and in each caserepresent hydrogen, alkyl or unsubstituted or substituted aryl,

Z represents a straight-chain or branched alkyl chain and

A represents hydrogen or an amino protective group,

M represents hydrogen, or represents an equivalent of a correspondingalkali metal cation, alkaline earth metal cation or ammonium cation and

X and X¹ are identical or different and represent oxygen or sulphur,

and their acid addition salts and metal salt complexes, with theexception of compounds in which A, R^(3'), R^(4'), R^(5') and R^(6')represent hydrogen, R^(2') represents carboxyl and R^(2') representsmethyl.

Formula (Ia) provides a general definition of the substituted2-cyclohexan-1-yl-amine derivatives which were hitherto unknown.

Preferred compounds of the formula (Ia) are those in which

R^(1') represents hydrogen, halogen or straight-chain or branched alkylhaving 1 to 6 carbon atoms,

R^(2') represents formyl, straight-chain or branched hydroxyalkyl having1 to 8 carbon atoms in the alkyl moiety, or represents one of theradicals ##STR8##

R^(3'), R^(4'), R^(5') and R^(6') are identical or different and in eachcase represent hydrogen, in each case straight-chain or branched alkylor alkoxy having 1 to 8 carbon atoms, alkoxyalkyloxy having 1 to 8carbon atoms in each of the individual alkyl moieties, or represent arylor aralkyl, each of which has 6 to 10 carbon atoms in the aryl moietyand if appropriate 1 to 4 carbon atoms in the alkyl moiety and each ofwhich is unsubstituted or monosubstituted to pentasubstituted in thearyl moiety by identical or different substituents, suitable arylsubstituents being: halogen, nitro, cyano, amino, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, C₁ -C₄ -alkylthio, halogeno-(C₁ -C₄)-alkyl, halogeno-(C₁-C₄)-alkoxy, halogeno-(C₁ -C₄)-alkylthio, each of which has 1 to 9identical or different halogen atoms, and di-(C₁ -C₄)-alkylamino,furthermore represent a heterocyclic 5- or 6-membered group from theseries comprising furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3- or 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,4- or1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl,each of which is bonded, if appropriate, via a methylene group and eachof which is unsubstituted or monosubstituted to trisubstituted byidentical or different substituents, suitable substituents for theheterocycle in each case being: halogen, nitro, cyano, amino, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy or C₁ -C₄ -alkylthio, halogeno(C₁ -C₄)-alkyl,halogeno-(C₁ -C₄)-alkoxy or halogeno(C₁ -C₄)-alkylthio, each of whichhas 1 to 9 identical or different halogen atoms, and di-(C₁-C₄)-alkylamino,

where at least two of the radicals R^(3'), R^(4'), R^(5') or R^(6')represent hydrogen,

R^(7') represents in each case straight-chain or branched alkyl oralkoxy having 1 to 6 carbon atoms,

R^(8') represents hydroxyl, straight-chain or branched hydroxyalkyloxyhaving 1 to 8 carbon atoms, straight-chain or branched halogenoalkyloxyhaving to 8 carbon atoms and 1 to 17 identical or different halogenatoms, or represents alkenylalkyloxy, alkinylalkyloxy and cycloalkyloxy,each of which has 3 to 6 carbon atoms and each of which is unsubstitutedor monosubstituted to polysubstituted by identical or different halogensubstituents, in each case straight-chain or branched alkoxy oralkylthio having 1 to 6 carbon atoms, or straight-chain or branchedalkoxyalkyloxy having 1 to 6 carbon atoms in each of the alkoxy or alkylmoieties, or represents aryloxy, arylthio, aralkyl or aralkyloxy, eachof which has 6 to 10 carbon atoms in the aryl moiety and if appropriateto 8 carbon atoms in the alkyl moiety and each of which is unsubstitutedor monosubstituted to pentasubstituted in the aryl moiety by identicalor different substituents, suitable aryl substituents being the arylsubstituents mentioned above, or represents a group --O--Z--NR^(10')R^(11'), --NR^(10') R^(11') or --OM,

R^(9') represents hydrogen or straight-chain or branched alkyl having 1to 6 carbon atoms,

R^(10') and R^(11') are identical or different and represent hydrogen,straight-chain or branched alkyl having 1 to 6 carbon atoms, or arylwhich has 6 to 10 carbon atoms and which is unsubstituted ormonosubstituted to pentasubstituted by identical or differentsubstituents, suitable aryl substituents being the aryl substituentsmentioned above,

M represents hydrogen or represents an equivalent of a correspondingalkali metal cation, alkaline earth metal cation or ammonium cation and

Z represents a straight-chain or branched alkyl chain having 1 to 8carbon atoms,

A represents hydrogen or an amino protective group, and

X and X¹ are identical or different and represent oxygen or sulphur,with the exception of compounds in which R^(3'), R^(4'), R⁵, R^(6') andA represent hydrogen, R^(2') represents carboxyl and R representsmethyl.

Other preferred compounds according to the invention are additionproducts of acids and those substituted 2-cyclohexan-1-yl-aminederivatives of the formula (Ia) in which R^(1'), R^(2'), R^(3'), R^(4'),R^(5') and R^(6') have the abovementioned meanings.

Other compounds according to the invention are those having thefollowing formula: ##STR9## in which

R^(2') represents the grouping ##STR10## or an acid addition salt ormetal said complex thereof.

The acids which can be added on preferably include hydrohalic acids suchas, for example, hydrochloric acid and hydrobromic acid, in particularhydrochloric acid, furthermore phosphoric acid, nitric acid, mono- andbifunctional carboxylic acids and hydroxycarboxylic acids such as, forexample, acetic acid, trifluoroacetic acid, maleic acid, succinic acid,fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acidand lactic acid, oleic acid, stearic acid, or benzoic acid which isoptionally monosubstituted or polysubstituted by nitro or halogen, orgluconic acid, ascorbic acid, malic acid, sulphamic acid, sulphonicacids such as, for example, p-toluenesulphonic acid,1,5-naphthalenedisulphonic acid and methanesulphonic acid, and alsoimides such as, for example, phthalimide, saccharin and thiosaccharin.

Other compounds to be preferably used according to the invention arefurthermore addition products of salts of metals of main groups I, IIand III and of tin, furthermore salts of metals of sub-groups I, II, VIIand VIII of the Periodic Table of the Elements and those substituted2-cyclohexan-1-yl-amine derivatives of the formula (Ia) in which R^(1'),R^(2'), R^(3'), R^(4'), R^(5') and R^(6') have the abovementionedmeanings.

In this context, salts of copper, zinc, manganese, magnesium, calcium,tin, iron, cobalt and of nickel are particularly preferred. Suitableanions of these salts are those which are derived from those acids whichlead to physiologically acceptable addition products. Acids of this typewhich are particularly preferred in this connection are the hydrohalicacids such as, for example, hydrochloric acid and hydrobromic acid,further phosphoric acid, nitric acid and sulphuric acid.

Particularly preferred compounds of the formula (Ia) are those in which

R^(1') represents straight-chain or branched alkyl having 1 to 4 carbonatoms or in particular hydrogen,

R^(2') represents formyl, straight-chain or branched hydroxyalkyl having1 to 4 carbon atoms in the alkyl moiety, or represents one of theradicals ##STR11## or, in particular ##STR12##

R^(3'), R^(4'), R^(5') and R^(6') are identical or different and in eachcase represent hydrogen, in each case straight-chain or branched alkylor alkoxy having 1 to 6 carbon atoms, alkoxyalkyloxy having 1 to 6carbon atoms in each of the individual alkyl moieties, or representphenyl or phenylalkyl, having, where appropriate, 1 or 2 carbon atoms inthe alkyl moiety, each of which is unsubstituted or monosubstituted totrisubstituted in the phenyl moiety by identical or differentsubstituents, suitable phenyl substituents being: fluorine, chlorine,bromine, nitro, cyano, amino, C₁ -C₂ -alkyl, C₁ -C₃ -alkoxy or C₁ -C₂-alkylthio, halogeno-(C₁ -C₂)-alkyl, halogeno-(C₁ -C₂)-alkoxy andhalogeno-(C₁ -C₂)-alkylthio, each of which has 1 to 5 identical ordifferent fluorine and/or chlorine atoms, and di-(C₁ -C₂)-alkylamino,furthermore represent a heterocyclic five- or six-membered group fromthe series comprising furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3- or 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,4- or1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl,each of which is, if appropriate, bonded via a methylene group and eachof which is unsubstituted or monosubstituted to trisubstituted byidentical or different substituents, suitable substituents for theheterocycle in each case being: fluorine, chlorine, bromine, nitro,cyano, amino, C₁ -C₂ -alkyl, C₁ -C₂ -alkoxy or C₁ -C₂ -alkylthio,halogeno-(C₁ -C₂)-alkyl, halogeno-(C₁ -C₂)-alkoxy, halogeno-(C₁-C₂)-alkylthio, each of which has 1 to 5 identical or different fluorineand/or chlorine atoms and di-(C₁ -C₂)-alkylamino,

--but in particular in each case represent hydrogen or in each casestraight-chain or branched alkyl having 1 to 4 carbon atoms--

where at least two of the radicals R^(3'), R^(4'), R^(5') and R^(6')represent hydrogen,

R^(7') in each case represents straight-chain or branched alkoxy or inparticular alkyl having 1 to 4 carbon atoms,

R^(8') represents hydroxyl, straight-chain or branched hydroxyalkyloxyhaving 1 to 6 carbon atoms, straight-chain or branched halogenoalkyloxyhaving 1 to 6 carbon atoms and 1 to 13 identical or different halogenatoms, or represents alkenylalkyloxy, alkinylalkyloxy and cycloalkyloxy,each of which has 3 to 6 carbon atoms and each of which is unsubstitutedor monosubstituted to trisubstituted by identical or differentsubstituents from the series comprising fluorine, chlorine and bromine,or represents in each case straight-chain or branched alkoxy oralkylthio having 1 to 4 carbon atoms, straight-chain or branchedalkoxyalkylalkoxy having 1 to 4 carbon atoms in each of the alkoxy oralkyl moieties, or represents phenyloxy, phenylthio, phenylalkyl orphenylalkyloxy, each of which has, if appropriate, 1 to 6 carbon atomsin the alkyl moiety and each of which is unsubstituted ormonosubstituted to trisubstituted in the phenyl moiety by identical ordifferent substituents, suitable phenyl substituents being the phenylsubstituents mentioned above, or represents a group --O--Z--NR^(10')R^(11'), --NR^(10') R^(11') or --OM,

--but in particular represents hydroxyl, in each case straight-chain orbranched alkoxy, alkoxyalkyloxy or phenylalkoxy, each of which has 1 to4 carbon atoms in the alkoxy or alkyl moiety--

R^(9') represents hydrogen or straight-chain or branched alkyl having 1to 4 carbon atoms,

R^(10') and R^(11') are identical or different and represent hydrogen,straight-chain or branched alkyl having 1 to 4 carbon atoms, orrepresent phenyl which is unsubstituted or monosubstituted totrisubstituted by identical or different substituents, suitable phenylsubstituents being the phenyl substituents mentioned above,

M represents hydrogen, or represents an equivalent of a correspondingalkali metal cation, alkaline earth metal cation or ammonium cation and

Z represents a straight-chain or branched alkyl chain having 1 to 6carbon atoms.

A represents hydrogen or an amino protective group, and

X and X¹ are identical or different and represent oxygen or sulphur,with the exception of compounds A, R^(3'), R^(4'), R^(5') and R^(6')represent hydrogen, R^(2') represents carboxyl and R^(1') representsmethyl.

The acid addition salts and metal salt complexes to be mentioned in thisconnection are those which have already been mentioned in thedescription of the preferred 2-cyclohexen-1-yl-amine derivatives of theformula (Ia) which were substituted according to the invention.

The substituted 2-cyclohexan-1-yl-amine derivatives of the formula (Ia)are obtained when

A) 2-cyclohexan-1-yl-amine derivatives of the formula (II) ##STR13## or

B) phenylamine derivatives of the formula (III) ##STR14## in which

R^(1'), R^(2'), R^(3'), R^(4'), R^(4'), R^(6') and A in each case havethe abovementioned meaning and

are hydrogenated in a generally customary manner with hydrogen attemperatures from 10° C. to 300° C. and pressures from 10 to 300 bar, ifappropriate in the presence of a diluent such as, for example, ethanol,dimethoxyethanol or tetrahydrofuran, and in the presence of a catalystsuch as, for example, ruthenium/carbon or rhodium on aluminium oxide.

The substituted 2-cyclohexan-1-yl-amine derivatives of the formula (Ia)in which

A represents hydrogen are furthermore obtained

C) from the 2-cyclohexane derivatives of the formula (Ia) ##STR15## inwhich

R^(1'), R^(2'), R^(3'), R^(4'), R^(5') and R^(6') have theabovementioned meaning and

A represents an amino protective group

in a manner known per se by customary methods, for example bysolvolysis, such as hydrolysis, acidolysis, by reduction such as, forexample, by hydrogenolysis in the presence of a hydrogenation catalystor by means of a reduction system comprising metal andproton-eliminating agetn, where, depending on the nature of theprotective group, various types (also other types) of eliminationmethods, also selective elimination methods, can be used, if appropriatein the presence of a suitable solvent or diluent or a mixture of these,the process being carried out, if required, with cooling, at roomtemperature or with heating, for example, in a temperature range fromabout -10° C. to the boiling point of the reaction medium, preferablyfrom about -10° C. about 150° C., and, if necessary, in a sealed vessel,under pressure, in an inert gas atmosphere and/or under anhydrousconditions,

and, if desired, the resulting products are converted into acid additionsalts or metal salt complexes (cf. Protective Groups in OrganicSynthesis, Th. W. Greene, Wiley Interscience, 1981).

The formyl, acetyl or 2,2,2-trichloroacetyl group which has beenmentioned, amongst others, as amino protective group, can be eliminatedfor example by hydrolysis.

The hydrolysis is effected in a manner known per se with the aid ofwater, this process being carried out advantageously in the presence ofan acid or base which aids hydrolysis, if appropriate in the presence ofan inert solvent or diluent, and/or with cooling or heating.

Examples of possible acids are inorganic acids such as mineral acids,for example sulphuric acid, phosphoric acid or hydrohalic acids, organiccarboxylic acids such as lower alkanecarboxylic acids, for exampleglacial acetic acid, such as optionally unsaturated dicarboxylic acids,for example oxalic, malonic, maleic or fumaric acid, or such ashydroxycarboxylic acids, for example tartaric acid or citric acid, orsulphonic acids, such as C₁ -C₇ -alkane- or optionally substitutedbenzenesulphonic acid, for example methane- or p-toluenesulphonic acid.

Examples of suitable bases are hydroxides, hydrides, amides,alkanolates, carbonates, triphenylmethylides, di-C₁ -C₇ -alkylamides,amino-C₁ -C₇ -alkylamides or C₁ -C₇ -alkylsilylamides of alkali metals,or naphthalene-amines, C₁ -C₇ -alkylamines, basic heterocycles, ammoniumhydroxides, and also carbocyclic amines. Examples which may be mentionedare lithium hydroxide, sodium hydroxide, sodium hydride, sodium amide,sodium ethylate, potassium tert-butylate, potassium carbonate, lithiumtriphenylmethylide, lithium diisopropylamide, potassium3-(aminopropyl)amide, potassium bis-(trimethylsilyl)-amide,dimethyl-aminonaphthalene, di- or triethylamine, pyridine,benzyl-trimethyl-ammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and also 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU).

The acidolysis can be carried out successfully, for example using strongacids, advantageously trifluoroacetic acid or perchloric acid, but alsoother strong inorganic acids such as hydrochloric acid or sulphuricacid, strong organic carboxylic acids such as trichloroacetic acid, orsulphonic acids such as benzene- or p-toluene sulphonic acid. It ispossible for an additional inert solvent to be present. Preferred inertsolvents which are suitable are organic solvents, for example carboxylicacids such as acetic acid, ethers such as tetrahydrofuran or dioxane,amides such as dimethylformamide (DMF), halogenated hydrocarbons such asdichloromethane, and furthermore also alcohols such as methanol, ethanolor isopropanol, and also water.

Mixtures of the abovementioned solvents are also suitable.Trifluoroacetic acid is preferably used in excess without adding afurther solvent, perchloric acid is preferably used in the form of amixture of acetic acid and 70% strength perchloric acid in a ratio of9:1. The reaction temperatures for these solvolyses are advantageouslybetween about 0° and about 50° C., the process is preferably carried outbetween 15° and 30° C. (room temperature).

For example, the BOC group can preferably be eliminated using 40%strength trifluoroacetic acid in methylene chloride, or approximately 3to 5N hydrochloric acid in dioxane at 15°-30° C., and the FMOC group(9-fluorenylmethyloxycarbonyl) using an approximately 5 to 20% strengthsolution of dimethylamine, diethylamine or piperidine indimethylformamide, at 15°-30° C. The DNP group (2,4-dinitrophenyl) canalso be eliminated successfully for example using an approximately 3 to10% strength solution of 2-mercaptoethanol in dimethylformamide/water,at 15°-30° C. Protective groups which can be detached by means ofhydrogenolysis (for example BOM, CBZ or benzyl) can be eliminated forexample by treatment with hydrogen in the presence of a catalyst (forexample a noble-metal catalyst such as palladium, expediently on asupport such as charcoal). Suitable solvents in this context are thesolvents mentioned above, in particular for example alcohols, such asmethanol or ethanol, or amides, such as dimethylformamide. As a rule,the hydrogenolysis is carried out at temperatures from about 0° to 100°C. and a pressure from about 1 to 200 bar, preferably 20° to 30° C. and1 to 10 bar. For example, hydrogenolysis on the CBZ group is carried outsuccessfully on 5 to 10% Pd/charcoal in methanol at 20°-30° C.

Examples of amino protective groups which are eliminated by means of areducing system of metal and protoneliminating agent are(4-nitro)-benzyloxycarbonyl, 2-iodo- or 2,2,2-trichloroethoxycarbonyl orphenacyloxycarbonyl.

The metal component of the metallic reducing system is, for example, abase metal, such as alkali metal or alkaline earth metal, for examplelithium, sodium, potassium, magnesium or calcium, or a transition metal,for example zinc, tin, iron or titanium, while suitableproton-eliminating agents are, for example, protonic acids of the typementioned above, such as hydrochloric acid or acetic acid, C₁ -C₇-alcohols, such as ethanol, and/or amines or ammonia. Examples of suchsystems are sodium/ammonia, zinc/hydrochloric or acetic acid, orzinc/ethanol.

Furthermore, 4-nitrobenzyloxycarbonyl can be split, for example, with adithionite, such as sodium dithionite, phenacyloxycarbonyl and2-halogeno-C₂ C₇ -alkanoyl, for example with the aid of a nucleophilicreagent, such as a thiolate, for example sodium thiophenolate, orthiourea and base, followed by hydrolysis, and allyl or but-2-enyl withthe aid of a rhodium(III) halide, such as rhodium-(III) chloride.

The compounds of the formula (I) which are known can be preparedanalogously to the new compounds of the formula (Ia).

If, for example, tert.-butyl(6-carbomethoxy-4-methyl-2-cyclohexen-1-yl)-carbonate, are used asstarting substances, the course of the reaction of preparation process(A) can be illustrated by the following equation: ##STR16## If, forexample, tert-butyl (4-methyl-2-carbomethoxycyclohexan-1-yl)carbamateand 1N sodium hydroxide solution are used as starting substances in afirst step and 1N hydrochloric acid in a second step, the course of thereaction of the preparation process (C) can be illustrated by thefollowing equation: ##STR17##

Formula (II) and formula (III) provide general definitions of the2-cyclohexen-1-yl-amine derivatives and the phenylamine derivatives,respectively, required as starting substances for carrying outpreparation process (A). In this formula (II) or formula (III), R^(2'),R^(3'), R^(4'), R^(5') and R^(6') and R^(1') in formula (II) preferably,or in particular, represent the substituents which have been mentionedabove in the description of the new 2-cyclohexan-1-yl-amine derivativesof the formula (Ia) as being preferred, or particularly preferred, forthese radicals.

The 2-cyclohexen-1-yl-amine derivatives of the formula (II) and thephenylamine derivatives of the formula (III) are known and can beprepared in a simple, analogous manner by known processes.

Processes A and B according to the invention for the preparation of thenew cyclohexane derivatives of the formula (Ia) are preferably carriedout using diluents.

Suitable diluents for this purpose are virtually all inert organicsolvents. These preferably include aliphatic and aromatic, optionallyhalogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane,petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylenechloride, ethylene chloride, chloroform, carbon tetrachloride,chlorobenzene and o-dichlorobenzene, ethers such as diethyl ether anddibutyl ether, glycol dimethyl ether and diglycol dimethyl ether,tetrahydrofuran and dioxane, and also dimethyl sulphoxide,tetramethylene sulphone and hexamethylphosphoric triamide.

Suitable inert gases for this purpose are nitrogen and virtually allnoble gases, in particular argon.

When carrying out processes A and B for the preparation of the2-cyclohexane derivatives of the formula (Ia), the reaction temperaturescan be varied within a substantial range. In general, the process iscarried out at temperatures between 10° C. and 300° C., preferablybetween 20° C. and 150° C.

For carrying out processes A and B for the preparation of the2-cyclohexane derivatives of the formula (Ia), hydrogen is employed inexcess and 0.1 to 5.0 moles of catalyst are preferably employed.

The process according to the invention for the preparation of2-cyclohexane derivatives of the formula (Ia) is generally carried outunder increased pressure. In general, the process is carried out under apressure from 1 to 300 bar, preferably at 5 to 200 bar.

Suitable catalysts for the preparation of the new2-cyclohexan-1-yl-carboxylic acid derivatives of the formula (Ia) inaccordance with process variants A and B are catalysts which arecustomary for reactions of this type; noble-metal catalysts such as, forexample, ruthium on carbon or rhodium on aluminium oxide are preferablyused.

However, under certain conditions, the process for the preparation ofthe new 2-cyclohexane derivatives of the formula (Ia) can also becarried out without diluents and a pressure from 1 to 200 bar.

In general, the reactions are carried out in a suitable diluent, and thereaction mixture is stirred for several hours at the particulartemperature required. Working-up is carried out in each case bycustomary methods. In general, the procedure is followed in which thereaction mixture is either concentrated under reduced pressure or pouredinto water, and the product is isolated by extraction or filtration andpurified by chromatography.

The compounds of the formula (I), and (Ia) can be obtained as mixturesof enantiomers or diastereomers.

The invention embraces the pure isomers as well as the mixtures. Thesemixtures of diastereomers can be separated into the components followingconventional methods, for example by selective crystallisation, fromsuitable solvents or chromatography on silica gel or aluminium oxide.Racemates can be resolved by customary methods to give the individualenantiomers, for example by salt formation with optically active acidssuch as camphorsulphonic acid or dibenzoyltartaric acid and selectivecrystallisation, or by derivatisation with suitable optically activereagents, separation of the diastereomeric derivatives, and recleavageor separation on optically active column material.

Suitable acids for the preparation of acid addition salts of thecompounds of the formula (Ia) are preferably those which have alreadybeen mentioned in connection with the description of the acid additionsalts according to the invention as being preferred acids.

The acid addition salts of the compounds of the formula (Ia) can beobtained in a simple manner by customary salt formation methods, forexample by dissolving a compound of the general formula (Ia) in asuitable inert solvent and adding the acid, for example hydrochloricacid, and they can be isolated in a customary manner, for example byfiltration, and, if appropriate, purified by washing with an inertorganic solvent.

Suitable salts of metals for the preparation of metal salt complexes ofthe compounds of the general formula (Ia) are preferably those whichhave already been described further above.

The metal salt complexes of compounds of the general formula (Ia) can beobtained in a simple manner by customary processes, for example bydissolving the metal salt in alcohol, for example ethanol, and addingthe solution to compounds of the general formula (Ia). Metal saltcomplexes can be isolated in a customary manner, for example byfiltration, and, if appropriate, purified by recrystallisation.

The active compounds of the formulae (I) and (Ia) which can be usedaccording to the invention and their acid addition salts have a powerfulbiological action and can be employed in practice for combatingundesired pests. For example, the active compounds can be employed foruse as plant protection agents, especially as fungicides.

Fungicidal agents in plant protection are employed for combatingPlasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes,Ascomycetes, Basidiomycetes and Deuteromycetes.

Some causative organisms of fungal and bacterial diseases which comeunder the generic names listed above may be mentioned as examples, butnot by way of limitation:

Xanthomonas species, such as, for example, Xanthomonas campestris pv.oryzae;

Pseudomonas species, such as, for example, Pseudomonas syringae pv.lachrymans;

Erwinia species, such as, for example, Erwinia amylovora;

Pythium species, such as, for example, Pythium ultimum;

Phytophthora species, such as, for example, Phytophthora infestans;

Pseudoperonospora species, such as, for example,

Pseudoperonospora humuli or Pseudoperonospora cubensis;

Plasmopara species, such as, for example, Plasmopara viticola;

Peronospora species, such as, for example, Peronospora pisi or P.brassicae;

Erysiphe species, such as, for example, Erysiphe graminis;

Sphaerotheca species, such as, for example, Sphaerotheca fuliginea;

Podosphaera species, such as, for example, Podosphaera leucotricha;

Venturia species, such as, for example, Venturia inaequalis;

Pyrenophora species, such as, for example, Pyrenophora teres or P.graminea (conidia form: Drechslera, syn: Helminthosporium);

Cochliobolus species, such as, for example, Cochliobolus sativus(conidia form: Drechslera, syn: Helminthosporium);

Uromyces species, such as, for example, Uromyces appendiculatus;

Puccinia species, such as, for example, Puccinia recondita;

Tilletia species, such as, for example, Tilletia caries;

Ustilago species, such as, for example, Ustilago nuda or Ustilagoavenae;

Pellicularia species, such as, for example, Pellicularia sasakii;

Pyricularia species, such as, for example Pyricularia oryzae;

Fusarium species, such as, for example, Fusarium culmorum;

Botrytis species, such as, for example, Botrytis cinerea;

Septoria species, such as, for example, Septoria nodorum;

Leptosphaeria species, such as, for example, Leptosphaeria nodorum;

Cercospora species, such as, for example, Cercospora canescens;

Alternaria species, such as, for example, Alternaria brassicae and

Pseudocercosporella species, such as, for example, Pseudocercosporellaherpotrichoides.

The good toleration, by plants, of the active compounds, at theconcentrations required for combating plant diseases, permits treatmentof above-ground parts of plants, of vegetative propagation stock andseeds, and of the soil.

As plant protection agents, the active compounds which can be usedaccording to the invention can be employed with particularly goodsuccess protectively, for combating Phytophthora species on tomatoes andVenturia species in apples.

Moreover, some of the active compounds which can be used according tothe invention have a good action against Pythium species, Alternariaspecies and Cercospora species.

Depending on their particular physical and/or chemical properties, theactive compounds which can be used according to the invention can beconverted into customary formulations, such as solutions, emulsions,suspensions, powders, foams, pastes, granules, aerosols, very finecapsules in polymeric substances and in coating compositions for seed,as well as ULV cold-mist and warm-mist formulations.

These formulations are produced in a known manner, for example by mixingthe active compounds with extenders, that is, liquid solvents, liquefiedgases under pressure, and/or solid carriers, optionally with the use ofsurface-active agents, that is, emulsifying agents and/or dispersingagents and/or foam-forming agents. In the case of the use of water as anextender, organic solvents can, for example, also be used as auxiliarysolvents. As liquid solvents, there are suitable in the main: aromatics,such as xylene, toluene, or alkylnaphthalenes, chlorinated aromatics orchlorinated aliphatic hydrocarbons, such as chlorobenzenes,chloroethylenes or methylene chloride, aliphatic hydrocarbons, such ascyclohexane or paraffins, for example mineral oil fractions, alcohols,such as butanol or glycol as well as their ethers and esters, ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone orcyclohexanone, strongly polar solvents, such as dimethylformamide anddimethyl sulphoxide, as well as water; by liquefied gaseous extenders orcarriers are meant liquids which are gaseous at ambient temperature andunder atmospheric pressure, for example aerosol propellants, such ashalogenated hydrocarbons as well as butane, propane, nitrogen and carbondioxide; as solid carriers there are suitable: for example groundnatural minerals, such as kaolins, clays, talc, chalk, quartz,attapulgite, montmorillonite or diatomaceous earth, and ground syntheticminerals, such as highly-disperse silica, alumina and silicates; assolid carriers for granules there are suitable: for example crushed andfractionated natural minerals such as calcite, marble, pumice, sepioliteand dolomite, as well as synthetic granules of inorganic and organicmeals, and granules of organic material such as sawdust, coconut shells,maize cobs and tobacco stalks; as emulsifying and/or foam-forming agentsthere are suitable: for example non-ionic and anionic emulsifiers, suchas polyoxyethylene fatty acid esters, polyoxyethylene fatty alcoholethers, for example alkylaryl polyglycol ethers, alkylsulphonates, alkylsulphates, arylsulphonates as well as albumen hydrolysis products; asdispersing agents there are suitable: for example lignin-sulphite wasteliquors and methylcellulose.

Adhesives such as carboxymethylcellulose and natural and syntheticpolymers in the form of powders, granules or latices, such as gumarabic, polyvinyl alcohol and polyvinyl acetate, as well as naturalphospholipids, such as cephalins and lecithins, and syntheticphospholipids, can be used in the formulations. Other additives can bemineral and vegetable oils.

It is possible to use colorants such as inorganic pigments, for exampleiron oxide, titanium oxide and Prussian Blue, and organic dyestuffs,such as alizarin dyestuffs, azo dyestuffs and metal phthalocyaninedyestuffs, and trace nutrients such as salts of iron, manganese, boron,copper, cobalt, molybdenum and zinc.

The formulations in general contain between 0.1 and 95 per cent byweight of active compound, preferably between 0.5 and 90%.

The active compounds which can be used according to the invention, assuch or in their formulations, can also be used for combating weeds asmixtures with known herbicides, finished formulations or tank mixesbeing possible.

Mixing with other known active compounds, such as fungicides,insecticides, acaricides, nematicides, bird repellants, plant nutrientsand agents which improve the soil structure, is also possible.

The active compounds can be used as such, in the form of theirformulations or in the use forms prepared therefrom by further dilution,such as ready-to-use solutions, suspensions, emulsions, powders, pastesand granules. They are applied in the customary manner, for example bywatering, spraying, atomising or scattering.

The active compounds which can be used according to the invention can beapplied before or after emergence of the plants.

They can also be incorporated into the soil before sowing.

The amount of active compound used can vary within a substantial range.It depends essentially on the nature of the desired effect. In general,the application rates are between 0.01 and 10 kg of active compound perhectare of soil area, preferably between 0.05 and 5 kg per ha.

Furthermore, the compounds of the formulae (I) and (Ia) which can beused according to the invention and their acid addition salts haveantimicrobial, in particular powerful antibacterial and antimycotic,actions. They have a very broad antimycotic spectrum of action, inparticular against dermatophytes and yeasts as well as biphasic fungi,for example against Candida species such as Candida albicans,Epidermophyton species such as Epidermophyton floccosum, Aspergillusspecies such as Aspergillus niger and Aspergillus fumigatus,Trichophyton species such as Trichophyton mentagrophytes, Microsporonspecies such as Microsporon felineum as well as Torulopsis species suchas Torulopsis glabrata. The enumeration of these microorganisms in nocase represents a limitation of the microorganisms which can becombated, but is of illustrative character.

Examples of indications in human medicine which may be mentioned are:dermatomycoses and systemic mycoses caused by Trichophytonmentagrophytes and other Trichophyton species, Microsporon species aswell as Epidermophyton floccosum, yeasts and biphasic fungi, as well asmoulds.

Indication areas which may be mentioned for example in veterinarymedicine are: All dermatomycoses and systemic mycoses, in particularthose caused by the abovementioned pathogens.

The present invention includes pharmaceutical preparations whichcontain, besides non-toxic inert pharmaceutically suitable excipients,one or more active compounds according to the invention, or whichconsist of one or more active compounds according to the invention.

The present invention also includes pharmaceutical preparations indosage units. This means that the preparations are in the form ofindividual portions, for example tablets, coated tablets, capsules,pills, suppositories and ampoules, whose active compound contentcorresponds to a fraction, or a multiple, of an individual dose. Thedosage units may contain, for example, 1, 2, 3 or 4 individual doses or1/2, 1/3 or 1/4 of an individual dose. An individual dose preferablycontains the amount of active compound which is administered in oneapplication and which usually corresponds to a whole, a half or a thirdor a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable excipients are understood asmeaning solid, semi-solid or liquid diluents, fillers or formulationauxiliaries of any type.

Preferred pharmaceutical preparations which may be mentioned aretablets, coated tablets, capsules, pills, granules, suppositories,solutions, suspensions and emulsions, pastes, ointments, gels, creams,lotions, powders or sprays.

Tablets, coated tablets, capsules, pills and granules can contain theactive substance, or active substances, besides the customary excipientssuch as (a) fillers and extenders, for example starches, lactose,sucrose, glucose, mannitol and silicare, (b) binders, for examplecarboxymethylcellulose, alginates, gelantine, polyvinylpyrrolidone, (c)humectants, for example glycerol, (d) disintegrants, for exampleagar-agar, calcium carbonate and sodium bicarbonate, (e) solutionretardants, for example paraffin, and (f) absorption accelerators, forexample quaternary ammonium compounds, (g) wetting agents, for examplecetyl alcohol or glycerol monostearate, (h) adsorbents, for examplekaolin and bentonite, and (i) lubricants, for example talc, calciumstearate and magnesium stearate, and solid polyethylene glycols, ormixtures of the substances mentioned under (a) to (i).

The tablets, coated tablets, capsules, pills and granules may beprovided with the customary optional opacifying agent-containingcoatings and shells and may be composed in such a way that they releasethe active compound, or preferably, in a particular part of theintestinal tract, in which case for example polymeric substances andwaxes can be used as embedding materials.

If appropriate, the active compound, or active compounds, may also bepresent in microencapsulated form with one or more of the abovementionedexcipients.

Suppositories may contain the customary water-soluble or water-insolubleexcipients, for example polyethylene glycols, fats, for example cocoafat, and higher esters (for example C₁₄ -alcohol with C₁₆ -fatty acid)or mixtures of these substances, in addition to the active compound, oractive compounds.

Ointments, pastes, creams and gels may contain the customary excipientsin addition to the active compound or active compounds, for exampleanimal and vegetable fats, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays may contain the customary excipients, for examplelactose, talc, silica, aluminium hydroxide, calcium silicate andpolyamide powder or mixtures of these substances, besides the activecompound or active compounds, and sprays may additionally contain thecustomary propellants, for example chlorofluorohydrocarbons.

Solutions and emulsions may contain, besides the active compound oractive compounds, the customary excipients such as solvents, solutionretardants and emulsifiers, for example water, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,oils, in particular cottonseed oil, groundnut oil, maize germ oil, oliveoil, castor oil and sesame oil, glycerol, glycerolformal,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions may also bepresent in sterile and blood-isotonic form.

Suspensions may contain, besides the active compound or activecompounds, the customary excipients such as liquid diluents, for examplewater, ethyl alcohol, propyl alcohol, suspending agents, for exampleethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters andpolyoxyethylene sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances.

The said formulation forms may also contain colorants, preservatives andodour-improving and flavour-improving additives, for example peppermintoil and eucalyptus oil, and sweeteners, for example saccharin.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical preparations in a concentration of about0.1 to 99.5, preferably from 0.5 to 95% by weight, of the total mixture.

Besides the active compounds according to the invention, theabovementioned pharmaceutical preparations may also contain furtherpharmaceutical active compounds.

The abovementioned pharmaceutical preparations are produced in acustomary manner by known methods, for example by mixing the activecompound or active compounds, with the excipient or the excipients.

The present invention also includes the use of the active compoundsaccording to the invention and also of pharmaceutical preparationscontaining one or more active compounds according to the invention, inhuman and veterinary medicine for the prophylaxis, improvement and/orcure of the abovementioned diseases.

The active compounds or the pharmaceutical preparations can beadministered locally, orally, parenterally, intraperitoneally and/orrectally, preferably parenterally, in particular intravenously.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compound or active compounds accordingto the invention in total amounts of about 2.5 to about 200, preferably5 to 150, mg/kg of body weight every 24 hours, if appropriate in theform of several individual doses, to obtain the desired results.

In the case of oral administrations, the active compounds according tothe invention are administered in total amounts of about 2.5 to about200, preferably 5 to 150 mg/kg of body weight every 24 hours, and in thecase of parenteral administration in total amounts of about 2.5 to about50, preferably 1 to 25 mg/kg of body weight every 24 hours.

However, it may be necessary to deviate from the said dosages, dependingon the species and the body weight of the subject to be treated, thenature and severity of the disease, the type of preparation, and theapplication of the medicament, and also the period or interval withinwhich the administration takes place. For example, in some cases it maybe sufficient to manage with less than the abovementioned amount ofactive compound, while in other cases the amount of active compoundindicated above must be exceeded. The optimum dosage required in eachcase and the type of administration of the active compounds can easilybe established by anyone skilled in the art on the basis of his expertknowledge.

The preparation and the use of the active compounds according to theinvention can be seen from the examples which follow.

PREPARATION EXAMPLES Example 1 (Process A) ##STR18##

A solution of 30 g (0.11 mol) of cis-tert.-butyl(4-methyl-6-carbomethoxy-2-cyclohexen-1-yl)-carbamate in 100 ml ofethanol is hydrogenated at room temperature and 30 bar H₂ until hydrogenuptake is complete. The catalyst is filtered off, the filtrate isevaporated to dryness, and 28 g (93% of theory) of cis-tert.-butyl(2-carbomethoxy-4-methylcyclohexan-1-yl)-carbamate having a meltingpoint of 74°-79° C. are obtained.

Example 2 ##STR19##

15 g (0.055 mol) of cis-tert.-butyl(2-carbomethoxy-4-methyl-2-cyclohexen-1-yl)-carbamate which have beenground finely in a mortar are suspended in 60 ml of 1N sodium hydroxidesolution and the suspension is stirred for 20 hours at 50° C. Aftercooling, the mixture is extracted once with diethyl ether, a pH of 1 isestablished in the aqueous phase at 0° C. using concentratedhydrochloric acid, and the solid is filtered off with suction. Afterwashing with water and drying, 13.3 g (94% of theory) of cis-tert.-Butyl(2-carboxy-4-methylcyclohexan-1-yl)-carbamate having a melting point of184°-188° C. are obtained.

Example 3 (Process C) ##STR20##

5 g (0.02 mol) of cis-tert.-butyl(2-carboxy-4-methylcyclohexan-1-yl)-carbamate are suspended in 20 ml of1N hydrochloric acid and the suspension is stirred for 12 hours at 55°to 60° C. After evaporation and drying in high vacuum, 3.7 g (96% oftheory) of cis-2-carboxy-4-methylcyclohexan-1-yl-amine hydrochloride areobtained as a white solid having a melting point of 218°-230° C.

Example 4 (Process B) ##STR21##

50 g (0.33 mol) of 2-amino-5-methyl-benzoic acid, dissolved in 100 ml oftetrahydrofuran, are hydrogenated for 14 hours at 200° C. and 200 barhydrogen in the presence of 5 g of ruthenium/charcoal. After cooling andevaporation, 30 g of 2-carboxy-4-methyl-cyclohexan-1-yl-amine areobtained as a pale oil.

¹ H NMR (200 MHz, CDCl₃): δ=0.85-0.98 (m, 3H); 1.05-2.00 (m, 9H);2.35-2.68 (m, 1H).

Example 5 ##STR22##

7.3 ml (0.1 mol) of thionyl chloride are added to 30 ml of methanol at-5° C. under N₂, and 15 g (0.096 mol) of2-carboxy-4-methylcyclohexan-1-yl-amine in 10 ml of methanol are thenadded dropwise to this solution at 0° C. After the mixture ha beenstirred under reflux for 12 hours it is cooled, a further 10 ml ofmethanol and 3 ml (0.04 mol) of thionyl chloride are added, and stirringunder reflux is continued for 4 hours. After cooling and evaporation todryness, 5 g of the residue is taken up in about 50 ml of diethyl etherand the mixture is washed in about 100 ml of cold 1N Naton lye andwater. The organic phase is dried and concentrated. 3.5 g (85% oftheory) of 2-carboxymethyl-4-methyl-cyclohexan-1-yl-amine are obtainedas a pale yellow oil.

¹ H NMR (200 MHz, CDCl₃): δ=3.70 (s, 3H, -CO₂ CH₃).

The end products of the formula (Ia) ##STR23## listed in Table 1 beloware obtained analogously to the methods described in Example to 5 andtaking into consideration the information in the description of theprocesses according to the invention.

    __________________________________________________________________________    Example No.                                                                          A            R.sup.1'                                                                          R.sup.2'         R.sup.3'                                                                         R.sup.4'                                                                         R.sup.5'                                                                         R.sup.6'                                                                         physical                 __________________________________________________________________________                                                         constant                  6     H × HCl                                                                              H   CO.sub.2 H       H  C.sub.2 H.sub.5                                                                  H  H  m.p.: 203°                                                             C.                        7     H × HCl                                                                              H   CO.sub.2 H       H  H  CH.sub.3                                                                         H  m.p. 183-237°                                                          C.                                                                            (isomer mixture)          8     H            H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer                9     H × Cu(OCOCH.sub.3).sub.2                                                            H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               10     H × HSO.sub.3 CH.sub.3                                                               H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               11     H × p-tolulsulphonic acid                                                            H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               12     H × HNO.sub.3                                                                        H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               13     H × HBF.sub.4                                                                        H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               14     H × CH.sub.2 (COOH).sub.2                                                            H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               15     H × HO.sub.2 CCO.sub.2 H                                                             H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               16     H × saccharin                                                                        H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               17     H × Na H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               18     H × NH.sub.3                                                                         H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               19     H            H                                                                                  ##STR24##       H  CH.sub.3                                                                         H  H  cis isomer               20     H            H                                                                                  ##STR25##       H  CH.sub.3                                                                         H  H  cis isomer               21     H            H                                                                                  ##STR26##       H  CH.sub.3                                                                         H  H  cis isomer               22     H            H                                                                                  ##STR27##       H  CH.sub.3                                                                         H  H  cis isomer               23     H            H   CO.sub.2 CH(CH.sub.3).sub.2                                                                    H  CH.sub.3                                                                         H  H  cis isomer               24     H × HCl                                                                              H   CO.sub.2 CH.sub.3                                                                              H  CH.sub.3                                                                         H  H  cis isomer               25     H × HCl                                                                              H                                                                                  ##STR28##       H  CH.sub.3                                                                         H  H  cis isomer               26     H × HCl                                                                              H                                                                                  ##STR29##       H  CH.sub.3                                                                         H  H  cis isomer               27     H × HCl                                                                              H                                                                                  ##STR30##       H  CH.sub.3                                                                         H  H  cis isomer               28     H × HCl                                                                              H                                                                                  ##STR31##       H  CH.sub.3                                                                         H  H  cis isomer               29     H × HCl                                                                              H   CO.sub.2 CH(CH.sub.3).sub.2                                                                    H  CH.sub.3                                                                         H  H  cis isomer               30     H × CF.sub.3 CO.sub.2 H                                                              H   COSCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                           H  CH.sub.3                                                                         H  H  isomer mixture           31     H × CF.sub.3 CO.sub.2 H                                                              H                                                                                  ##STR32##       H  CH.sub.3                                                                         H  H  isomer mixture           32     H × HCl                                                                              H   CO.sub.2 Me      H  CH.sub.3                                                                         H  H  isomer mixture           33     H × CF.sub.3 CO.sub.2 H                                                              H   CONHCH(CH.sub.3)CO.sub.2 C.sub.2 H.sub.5                                                       H  CH.sub.3                                                                         H  H  isomer mixture           34     H × HCl                                                                              H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  (-)-Enantiomer           35     H × HCl                                                                              H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  (+)-Enantiomer                                                                [α].sub.D =                                                             +53,2                                                                         (C = 1; H.sub.2 C)       36     H × HCl                                                                              H   CO.sub.2 Et      H  CH.sub.3                                                                         H  H  cis isomer               37     H            H   CO.sub.2 CH.sub.2 C CH                                                                         H  CH.sub.3                                                                         H  H  cis isomer               38     COCH.sub.3   H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer                                                                    Fp.: 216° C.      39     COCH(NH.sub.2)CH.sub.3                                                                     H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  cis isomer               40     H × HCl                                                                              H   CO.sub.2 H       H  H  C.sub.2 H.sub.5                                                                  H  Fp.: 206-30°                                                           C.                       41     H            H   CO.sub.2 H       H  CH.sub.3                                                                         H  H  [α].sub.D =                                                             38.9                                                                          (C = 1; H.sub.2          __________________________________________________________________________                                                         O)                   

Preparation of the Starting Compounds ##STR33##

A solution of 10 g (0.05 mol) of methyl2-carboxy-5-methylcyclohex-3-ene-carboxylate and 8 g (0.062 mol) ofN,N-diisopropylethylamine in 30 ml of acetone is treated at -5° C. inthe course of 30 minutes with a solution of 5.4 g (0.05 mol) of ethylchloroformate in 15 ml of acetone. After a further 30 minutes at 0° C.,an ice-cooled solution of 6.5 g (0.1 mol) of sodium azide in 15 ml ofwater is added dropwise. The mixture is stirred for 15 minutes at 0° C.and then worked up using water/toluene.

The toluene phase which has been concentrated to about 50 ml is thenadded dropwise to a refluxed solution of 3 g (0.04 mol) of tert-butanoland 25 mg (0.15 mmol) of tert-butylcatechol in 20 ml of toluene. Thecourse of the reaction is monitored by means of IR spectroscopy.

The mixture is allowed to cool to room temperature and is concentrated.After separation by column chromatography on silica gel using petroleumether/ethyl acetate (6 : 1) as the mobile phase, 4 g (30% of theory) oftert-butyl (4-methyl-6-carbomethoxy-2-cyclohexen-1-yl)-carbamate ofmelting point 89°-91° C. are obtained.

Example A

Phytophthora test (tomato) /protective

Solvent 4.7 parts by weight of acetone

Emulsifier : 0.3 parts by weight of alkyl-aryl polyglycol ether

To prepare a suitable preparation of active compound, 1 part by weightof active compound is mixed with the stated amounts of solvent andemulsifier, and the concentrate is diluted with water to the desiredconcentration.

To test for protective activity, young plants are sprayed with thepreparation of active compound until dripping wet. After the spraycoating has dried on, the plants are inoculated with an aqueous sporesuspension of Phytophthora infestans.

The plants are placed in an incubation cabin at 100% relativeatmospheric humidity at about 20° C.

The evaluation takes place 3 days after inoculation.

At an active compound concentration of 10 ppm, the degree ofeffectiveness of compounds 3, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and18 is higher than 90%.

Example B

Pythium sp. test (peas) /seed treatment

The active compounds are applied in the form of agents for dryseed-dressing. They are prepared by extending the active compound inquestion with ground minerals to give a finely pulverulent mixture whichguarantees even distribution on the seed surface.

For the seed dressing, the seeds together with the seed-dressing agentare shaken for 3 minutes in a sealed glass flask.

Seeds are sown at the rate of 2×50 grains in a depth of 2 cm in anaturally Pythium sp.-infected compost soil and grown in a greenhouse ata temperature of about 20° C. in seed boxes which are exposed to thelight for 15 hours per day.

The test is evaluated after 14 days.

At a dosage rate of active compound of 250 mg/kg seed, compound 3 showsan outstanding action.

What is claimed is:
 1. A substituted cyclohexan-1-yl-amine derivative ofthe formula ##STR34## in which R^(2') represents the grouping ##STR35##or an acid addition salt or metal salt complex thereof.
 2. A compoundaccording to claim 1, wherein such compound is the substitutedcyclohexan-1-yl-amine derivative of the formula ##STR36##
 3. A compoundaccording to claim 1, wherein such compound is the substitutedcyclohexan-1-yl-amine derivative of the formula ##STR37##
 4. A compoundaccording to claim 1, wherein such compound is the substitutedcyclohexan-1-yl-amine derivative of the formula ##STR38##
 5. A compoundaccording to claim 1, wherein such compound is the substitutedcyclohexan-1-yl-amine derivative of the formula ##STR39## ##STR40##
 6. Amicrobicidal composition comprising a microbicidally effective amount ofa compound or addition product thereof according to claim 1 and adiluent.
 7. A method of combating microbes which comprises applying tosuch microbes or to a locus from which it is desired to exclude suchmicrobes a microbicidally effective amount of a compound or additionproduct thereof according to claim 1.